Monoamine Regulation of Cortical Circuitry. The studies in this project are directed equally at examining structural deficits in schizophrenic prefrontal cortex at the cellular level and at elucidating prefrontal neural circuits that have been implicated in schizophrenia. The proposed studies will test the hypothesis that dysregulation of modulatory neurotransmitters, particularly dopamine and serotonin, produce dystrophic changes in cortical pyramidal and/or non-pyramidal neurons related to those observed in schizophrenia. To enhance our understanding of the neuropathology of schizophrenia at the cellular level, in Specific Aim 1 we propose to take a new approach-intracellular injection of selected neurons in fixed slices of postmortem tissue from patients and controls. After filling with Lucifer Yellow, double-label immunohistochemical procedures will be applied to visualize the dendritic arbors of selected pyramidal cells and their modulatory inputs (dopamine, serotonin and Substance P). Results from the immunohistochemical approach will be supplemented by stereological morphometry and the Golgi technique in the same blocks of tissue to correlate changes in dendritic morphology, cell size and packing density and modulatory inputs in supragranular layers of postmortem prefrontal cortex in schizophrenic brains. The second aim will conduct corollary studies in non-human primates with experimentally induced neurotransmitter dysregulation (EIND) and normal control monkeys, designed to elucidate the mechanisms for specific abnormalities observed in schizophrenic brain. This aim will employ same methods and quantitative approaches used in the postmortem studies. Specific Aims 2 will employ a "living-then-fixed" slice preparation developed in this laboratory to study local circuit interactions between selected pyramidal and non- pyramidal neurons in the supragranular layers of prefrontal cortex, where pathology has been demonstrated in schizophrenia. Finally, in Specific Aim 4, we will examine electron-microscopically the source of intrinsic and extrinsic afferents that interact with the D1 receptor and related signaling proteins. This receptor which is located predominantly in dendritic spines has been reported to be decreased in schizophrenia and is regulated by both the typical and atypical drugs that are used to treat schizophrenia. Collectively, the proposed studies are designed to be directly relevant to the issues of neuropathology in schizophrenia and, in addition, expand fundamental knowledge about cortical circuitry in association cortex.